Candida albicans is the most important fungal pathogen infecting humans. This fungal pathogen causes vaginal yeast infections, as well as oral infections and tissue invasion in immunocompromised patients. Oral infections are highly prevalent in AIDS patients and in cancer patients undergoing bone marrow replacement therapy. Only three types of anti-fungal drugs are currently approved for use in humans. Unfortunately, these anti-fungal drugs have serious side effects and have limited efficacy.
Yeast Saccharomyces cerevisiae strains that express DNA topoisomerase I and are permeable to the anti-tumor alkaloid camptothecin compounds are killed by the compound (Nitiss, et al., Proc. Natl. Acad. Sci. USA, 1988, 85, 7501-7505). Yeast strains which are permeable to camptothecin but lack topoisomerase I can establish sensitivity to camptothecin by expression of human DNA topoisomerase I (Bjornsti, et al., Cancer Res., 1989, 49, 6318-6323). Thus, yeast cells lacking endogenous topoisomerase I are killed by camptothecin if they express human topoisomerase I. Camptothecin kills such yeast strains by stabilizing a covalent topoisomerase I-DNA conjugate which leaves a broken DNA strand. The broken single strand can be processed to a double-strand break during DNA replication. If this damage is not repaired by DNA recombination, it leads to cell death. Camptothecin, however, is not a candidate for human therapy for fungal-associated conditions due to its activity on human topoisomerase I.
There is a need for compounds which selectively inhibit C. albicans topoisomerase I activity but which do not inhibit human topoisomerase I activity. There is a need for kits and methods of identifying such compounds. There is a need for isolated C. albicans topoisomerase I protein, and for compositions and methods of producing and isolating C. albicans topoisomerase I protein. There is a need for methods of treating individuals that have fungal infections.